Pharmacologic Antagonism of the Oral Aversive Taste-Directed Response to Capsaicin in a Mouse Brief Access Taste Aversion Assay

• Published in: The Journal of pharmacology and experimental therapeutics 2010-02, Vol.332 (2), p.525-530
• Main Authors: Long, Daniel J, Devantier, Heather R, Brennan, Francis X, Bryant, Robert W, Salemme, F Raymond, Palmer, R Kyle
• Format: Article
• Language: English
• Subjects: Acrylamides - pharmacology; Administration, Oral; Alkaloids; Anilides - pharmacology; Animals; Avoidance Learning - drug effects; Benzodioxoles; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Capsaicin - administration & dosage; Capsaicin - analogs & derivatives; Capsaicin - antagonists & inhibitors; Capsaicin - pharmacology; Cinnamates - pharmacology; Diterpenes - pharmacology; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Polyunsaturated Alkamides; Pyrazines - pharmacology; Pyridines - pharmacology; Taste - drug effects; TRPM Cation Channels - genetics; TRPV Cation Channels - agonists; TRPV Cation Channels - antagonists & inhibitors
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.109.155416

Chemosensory signaling by the tongue is a primary determinant of ingestive behavior and is mediated by specific interactions between tastant molecules and G protein-coupled and ion channel receptors. The functional relationship between tastant and receptor should be amenable to pharmacologic methods and manipulation. We have performed a pharmacologic characterization of the taste-directed licking of mice presented with solutions of capsaicin and other transient receptor potential vanilloid-1 (TRPV1) agonists using a brief access taste aversion assay. Dose-response functions for lick-rate suppression were established for capsaicin (EC 50 = 0.5 μM), piperine (EC 50 = 2 μM), and resiniferatoxin (EC 50 = 0.02 μM). Little or no effect on lick rate was observed in response to the full TRPV1 agonist olvanil. Capsaicin lick rates of wild-type and transient receptor potential melastatin-5 (TRPM5) knockout mice were equivalent, indicating that TRPM5, a critical component of aversive signaling for many bitter tastants, did not contribute to the capsaicin taste response. The selective TRPV1 antagonists N -(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2 H )-carbox-amide (10 μM) and ( E )-3-(4- t -butylphenyl)- N -(2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl)acrylamide (AMG9810) (10 μM) effectively blocked capsaicin- and piperine-mediated lick suppression. However, ( E )-3-(4-chlorophenyl)- N -(3-methoxyphenyl)- N -phenylprop-2-enamide (SB 366791) and capsazepine, also TRPV1 antagonists, were without effect at test concentrations of up to 30 and 100 μM, respectively. Our results demonstrate that TRPV1-mediated oral aversiveness presents a pharmacologic profile differing from what has been reported previously for TRPV1 pain signaling and, furthermore, that aversive tastes can be evaluated and controlled pharmacologically.